TECHNICAL FIELD

[0002] The present invention relates generally to the treatment or prevention of intracellular infections. More particularly, the invention relates to the treatment or prevention of intracellular infections by bacteria of the genus Mycobacterium, such as Mycobacterium tuberculosis (which causes tuberculosis) and Mycobacterium leprae (which causes leprosy), including strains that are resistant to conventional antimicrobials. The invention additionally relates to the treatment of immunocompromised patients infected by these and other mycobacteria species, including species (such as Mycobacterium avium, Mycobacterium aurum, and Mycobacterium smegmatis ) that are not pathogenic to immunocompetent individuals but may cause disease in immunocompromised patients.

BACKGROUND

[0003] Intracellular bacteria of the genus Mycobacterium are responsible for several serious and debilitating diseases, including tuberculosis and leprosy. Tuberculosis is a contagious bacterial infection caused by M. tuberculosis that afflicts millions of people worldwide. Current treatment regimens involve the daily administration of three or four antibiotics (e.g., combinations of rifampin, isoniazid, streptomycin, ethambutol, and pyrazinamide) for six to twelve months. Such regimens commonly produce significant adverse effects and low patient compliance. The low patient compliance in turn often leads to the development of drug-resistant strains. There is therefore a need for an improved method of treating patients suffering from tuberculosis that involves a simpler and shorter dosing regimen using a low-toxicity agent; such a regimen should lead to high patient compliance and a low incidence of emergent drug resistance.

[0004] Leprosy, a debilitating and disfiguring disease that affects skin and nerve tissue, is caused by M. leprae . The current treatment for leprosy resembles tuberculosis combination therapy, comprising administration of three or four antibiotics (e.g., combinations of dapsone, rifampin, rifampicine, and clofazimine). Due to the complexity of the current dosing regimen and its high expense, patient compliance tends to be low, leading to the emergence of drug-resistant strains. These problems, as with tuberculosis, are compounded by the high concentration of leprosy in developing countries, where medical supplies and education are commonly in short supply.

[0005] Although mycobacterial species pose serious threats to healthy individuals, the threats are greater for immunocompromised patients. These patients, such as those infected by HIV, are highly susceptible to mycobacterial infections and are less responsive to conventional combination anti-mycobacterial therapies. Therefore, there is a need for a more effective method of treating mycobacterial infections in immunocompromised patients. Further, an anti-mycobacterial agent must be compatible with ongoing therapies in these patients.

[0006] Gallium is known to prevent the replication of intracellular pathogens, including mycobacteria (Olakanmi et al., 1997, “Gallium inhibits growth of pathogenic mycobacteria in human macrophages by disruption of bacterial iron metabolism: a new therapy for tuberculosis and Mycobacterium avium complex?”, J Invest Med 45:234A). Without in any way restricting the invention to a particular mechanism of action, it is thought that gallium exerts its antibacterial activity through a novel mechanism: interference with bacterial iron uptake and metabolism through mimicry of ferric iron. Replicating bacterial cells (as other replicating cells) have a high iron requirement, due mainly to their need to produce ribonucleotide reductase (RR), a ferric iron-bearing enzyme essential for the synthesis of DNA. Gallium is chemically very similar to ferric iron, and so can be mistakenly taken up by these cells and incorporated into RR instead of iron. As gallium-containing RR (or iron-free RR in general) is nonfunctional, DNA cannot be synthesized and the affected cell attempting to replicate will ultimately undergo apoptosis.

[0007] In the case of tuberculosis, infecting mycobacteria live primarily within macrophages, making the bacteria particularly hard to reach and to treat with most antibacterial compounds. Macrophages, however, particularly those that are infected, naturally take up large amounts of iron by overexpressing transferrin receptor, which binds to the iron transport protein transferrin. Gallium administered orally as gallium maltolate binds to transferrin in place of iron, and so can gain entry into the macrophages and be taken up by the infecting mycobacteria. It is also possible that gallium administered as gallium maltolate can be taken up by macrophages and other target tissues by non-transferrin dependent mechanisms. The therapeutic mechanisms of action for gallium are discussed by Bernstein (1998), “Mechanisms of therapeutic activity for gallium”, Pharmacol Rev 50:665-682.

[0008] Gallium nitrate has been administered to humans by intravenous infusion, though with significant potential side effects such as nephrotoxicity. This is because a significant fraction of gallium from intravenous gallium nitrate circulates as the gallate radical (Ga(OH) ₄ ⁻ ). Gallate, as a small charged molecule, is rapidly excreted in the urine and can transiently reach high concentrations in the kidney, where it can react to form precipitates (see Webster et al. (1999), “A pharmacokinetic and phase II study of gallium nitrate in patients with non-small cell lung cancer”, Cancer Chemother Pharmacol 45: 55-58). Free gallium is also unavailable for target cell uptake by transferrin-dependent mechanisms. In addition, compliance for a drug requiring slow intravenous infusion, such as intravenous gallium nitrate, can be problematic over the several months required for conventional anti-mycobacterial therapy. By contrast, orally administered gallium maltolate provides a novel, safer, and potentially more effective alternative to the anti-mycobacterial agents currently in use or to gallium salts such as gallium nitrate that require intravenous administration. Due its unique mechanism of action, and the likely synergy of gallium with other antibiotics, oral gallium maltolate should also significantly shorten the course of treatment for mycobacterial infections. Thus, administration of gallium maltolate provides an improved method of treating patients suffering from mycobacterial infections, such as tuberculosis and leprosy, by providing a simpler as well as a shorter dosing regimen.

SUMMARY OF THE INVENTION

[0009] One aspect of the invention relates to a method of treating a patient infected by a prokaryote of the genus Mycobacterium by administering a therapeutically effective amount of a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone.

[0010] Yet another aspect of the invention relates to an improved method of treating a patient infected by a prokaryote of the genus Mycobacterium by administering to the patient a combination of antimicrobial agents selected from the group consisting of amikacin, aminosalicylic acid, azithromycin, capreomycin, ciprofloxacin, clarithromycin, clofazimine, cycloserine, dapsone, erythromycin, ethambutol, ethionamide, isoniazid, kanamycin, minocycline, ofloxacin, protionamide, pyrazinamide, rifabutin, rifampicine, rifampin, sparfloxacin, streptomycin, trimethoprim sulfamethoxazole, tobramycin, and viomycin; the improvement comprising administering a therapeutically effective amount of a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone.

[0011] Another aspect of the invention pertains to a method of treating an immunocompromised patient infected by a prokaryote of the genus Mycobacterium by administering a therapeutically effective amount of a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone.

[0012] Yet another aspect of the invention relates to a method of preventing infection by a prokaryote of the genus Mycobacterium by administering a prophylactically effective amount of a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone.

DETAILED DESCRIPTION OF THE INVENTION

[0013] As noted above, the present invention is directed to methods for treating and preventing infection by pathogenic intracellular prokaryotes of the genus Mycobacterium using a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone.

[0014] Examples of mycobacterial species to which the methods of the invention find utility include, by way of illustration and not limitation, M. leprae and M. tuberculosis.

[0015] Prior to discussing this invention in further detail, the following terms will be defined. Unless defined below, the terms used herein have their normally accepted meanings.

DEFINITIONS

[0016] As used herein, the following terms have the definitions given below:

[0017] The term “genus Mycobacterium” is intended to include all members of that genus including strains that are resistant to conventional antimicrobials. The term is intended to encompass species such as M. tuberculosis and M. leprae , as well as species such as M. avium, M. aurum , and M. smegmatis , which are not typically pathogenic to healthy or immunocompetent individuals but that may cause disease in immunocompromised patients. In general, the mycobacterial species of interest include, by way of illustration and not limitation, M. africanum, M. aurum, M. avium, M. avium paratuberculosis, M. balnei, M. bovis, M. chelonae, M. genitalium, M. gallisepticum, M. gastri, M. goodii, M. gordonae, M. haemophilum, M. intracellulare, M. kansasii, M. leprae, M. lepraemurium, M. malmoense, M. microti, M. penetrans, M. platypoecilus (commonly known as M. marinarum ), M. pneumoniae, M. scrofulvaeum, M. simiae, M. smegmatis, M. szulgai, M. terrae - trivial, M. tuberculosis, M. ulcerans , and M. xenopi.

[0018] The term “neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone” refers to an electrostatically neutral complex of Ga ³⁺ (Ga(III)) and three equivalents of the anionic form of a 3-hydroxy-4-pyrone, which complex is represented by the formula [Ga ³ +(py ⁻ ) ₃ ], wherein py ⁻ represents the anionic form of a 3-hydroxy-4-pyrone as defined below. Because such complexes do not dissociate to any significant extent in aqueous solutions maintained at a pH of from about 5 to about 9, these complexes remain predominantly electrostatically neutral in such solutions.

[0019] The term “3-hydroxy-4-pyrone” refers to a compound of Formula 1: 1

[0020] wherein R ¹ , R ² , and R ³ are independently selected from the group consisting of hydrogen and a —C _1-6 alkyl group. The —C _1-6 alkyl group can be branched or unbranched but is preferably unbranched. Suitable —C _1-6 alkyl groups include, by way of illustration and not limitation, methyl, ethyl, isopropyl, and n-propyl. Preferred —C _1-6 alkyl groups are those having 1-3 carbons, in particular, methyl, and ethyl. Single substitution is preferred, particularly substitution at the 2or the 6-position, with substitution at the 2-position being most preferred.

[0021] Exemplary compounds encompassed by the term “a 3-hydroxy-4-pyrone” are described below.

[0022] The unsubstituted form of Formula 1 (R ¹ , R ² , and R ³ are H) is known as pyromeconic acid.

[0023] Compounds of Formula 1 where R ² and R ³ are H include: 3-hydroxy-2-methyl-4-pyrone (R ¹ is —CH ₃ ), which is also known as maltol or larixinic acid; and 3-hydroxy-2-ethyl-4-pyrone (R ¹ is —C ₂ H ₅ ), which is sometimes referred to as ethyl maltol or ethylpyromeconic acid. Both of these are preferred for use in the methods of the invention, in particular 3-hydroxy-2-methyl-4-pyrone.

[0024] Compounds of Formula 1 where R ¹ and R ³ are H include 3-hydroxy-6-methyl-4-pyrone (R ² is —CH ₃ ).

[0025] The term “an anion of a 3-hydroxy-4-pyrone” refers to a compound defined in Formula 1 above wherein the hydroxyl proton has been removed so as to provide for the anionically charged form of the compound.

[0026] The term “administering” is intended to refer to the oral administration of any conventional form for the oral delivery of a pharmaceutical composition to a patient (e.g., human or other mammal) that results in the deposition of the pharmaceutical composition into the gastrointestinal tract (including the gastric portion of the gastrointestinal tract, i.e., the stomach) of the patient.

[0027] By the term “therapeutically effective” amount of a drug is meant a nontoxic but sufficient amount of a compound to provide the desired effect at a reasonable benefit/risk ratio. The desired effect may be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In particular, a therapeutically effective amount refers to an amount of gallium complex administered such that a blood plasma gallium concentration is obtained that is sufficient to enable treatment or prevention of the infection of interest. The therapeutically effective amount necessary to prevent a disease is referred to as the “prophylactically effective amount”.

[0028] The term “therapeutic agent” refers to any additional therapeutic agent that is co-administered with the neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone in the methods of the invention. The additional therapeutic agent can be administered by any route or in any dosage form. Co-administration can be by simultaneous or subsequent administration. Simultaneous administration can be in the form of separate or combined dosage forms, with the caveat that a combined dosage form should be suited for oral administration since that is the preferred route of delivery for the neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone.

[0029] The term “treat,” as in to “treat” a condition, is intended to include (1) preventing the condition, i.e., avoiding any clinical symptoms of the condition, (2) inhibiting the condition, that is, arresting the development or progression of clinical symptoms, and/or (3) relieving the condition, i.e., causing regression of clinical symptoms.

[0030] The term “patient”, as in “treatment of a patient”, is intended to refer to an individual animal or human afflicted with or prone to a condition, disorder, or disease as specified herein, and typically refers to mammals, particularly humans.

[0031] By “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone (and any additional therapeutic agents) without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0032] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, recitation of an additive as “optionally present” in a formulation herein encompasses both the formulation containing the additive and the formulation not containing the additive.

[0033] The term “immunocompromised patient” is intended to refer to a patient suffering from an immunodeficiency. This includes a patient who has an autoimmune disease such as systemic lupus erythematosus or rheumatoid arthritis, a patient who is infected with a retrovirus, a patient who is undergoing chemotherapy, a patient with a genetic mutation that predisposes him or her to an immunodeficient state, or a patient who is a transplant recipient taking anti-rejection medications. Retroviruses that may be the causative agent in producing an immunodeficiency in a patient include but are not limited to, the human spumavirus, Mason-Pfizer monkey bovine leukaemia virus, mouse mammary tumor virus, avian leukosis virus, murine leukemia virus, Rous sarcoma virus, feline leukemia virus, feline immunodeficiency virus, simian immunodeficiency virus, human T cell leukemia viral species (“HTLV1”, “HTLV2”), and human immunodeficiency virus (“HIV”). Of particular interest is HIV, which refers to one or more members of the group of retroviruses that are members of the primate lentivirus group of the genus Lentiviridae and are capable of infecting a human, whether or not this capability has been demonstrated. For example, HIV-1 and HIV-2 are examples of primate lentiviruses that are known to infect humans. Infection of a human by a lentivirus that is not named and differs from all known HIV strains is also considered to be within the scope of the invention.

[0034] It must be noted that as used herein and in the claims, the singular forms “a”, “and”, and “the” include reference to both the singular and plural unless the context clearly dictates otherwise. Thus, for example, reference to “a therapeutic agent” in a formulation includes two or more active agents, reference to “a carrier” includes two or more carriers, and so forth.

Synthesis And Methodology

[0035] The neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone useful in the methods of the present invention can be easily synthesized by methods that are well known in the art. U.S. Pat. No. 6,004,951 to Bernstein describes the synthesis of neutral 3:1 gallium complexes of the compounds of Formula 1, and is incorporated herein by reference. In general, the complexes are synthesized by reacting the desired 3-hydroxy-4-pyrone with gallium ions in solution. The gallium ions can be derived from a gallium salt, such as a gallium halide or gallium nitrate compound. The 3-hydroxy-4-pyrone starting materials either occur naturally or may be obtained commercially or by known synthetic methods. Typical solvents include water, ethanol, methanol, and chloroform. The hydroxypyrone and the gallium ions are mixed in 3:1 molar proportions, preferably with a slight excess of hydroxypyrone to insure a complete reaction of all the gallium.

Pharmaceutical Compositions and Modes of Administration

[0036] The methods of this invention are achieved by using a pharmaceutical composition comprising a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone. Preferred complexes include, by way of illustration and not limitation, the 3:1 complex of maltol with gallium, which is referred to as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium or gallium maltolate; and the 3:1 complex of ethyl maltol with gallium, referred to as tris(3-hydroxy-2-ethyl-4H-pyran-4-onato)gallium or gallium ethyl maltolate.

[0037] The compounds may be administered orally, parenterally (including by subcutaneous, intravenous, and intramuscular injection), transdermally, rectally, nasally, opthalmically, buccally, sublingually, topically, vaginally, etc., in dosage formulations containing one or more conventional nontoxic pharmaceutically acceptable carriers. For example, topical application to cutaneous lesions, such as the lesions caused by leprosy, is contemplated. The typical delivery route, however, is oral.

[0038] Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid, or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions contain an effective amount of the neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone, generally although not necessarily in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc. Various dosage forms of neutral 3:1 gallium complexes of a 3-hydroxy-4-pyrone suitable for use in the methods of the instant invention are set forth by Bernstein, U.S. Pat. No. 6,004,951.

[0039] As noted above, preferred compositions herein are oral formulations, which include delayed release oral formulations. While the neutral 3:1 complex of gallium with 3-hydroxy-4-pyrones delivers gallium to the bloodstream from the gastrointestinal tract, partial dissociation may occur of the neutral 3:1 complex of gallium with 3-hydroxy-4-pyrone under acidic conditions (generally at a pH of about 4 or less). Such acidic conditions may be present in the stomach. The dissociation may result in formation of less absorbable complexes, together with free hydroxypyrone and ionic gallium. Accordingly, in order to maintain the orally delivered gallium in a form that is highly absorbable in the gastrointestinal tract, the pharmaceutical compositions of this invention may be formulated to contain a means to inhibit dissociation of this complex when exposed to the acidic conditions of the stomach. Means to inhibit or prevent dissociation of this complex when exposed to the acidic conditions of the stomach are described in detail by Bernstein, U.S. Pat. No. 6,004,951. Suitable compositions can include a buffering agent that is effective to shift the equilibrium towards the neutral 3:1 complex within a mixture of gallium hydroxypyrone complexes (including the 1:1, 2:1, and 3:1 complexes), which may result when the composition reaches acidic conditions in the stomach of the individual. Another means of inhibiting or preventing dissociation is to encapsulate the pharmaceutical composition in a material that does not dissolve until the small intestine of the individual is reached, such as with enteric coated tablets, granules, or capsules, as is well known in the art.

Methods of Pharmaceutical Treatment

[0040] In general, the therapeutic plasma levels of gallium are approximately 1 to 5,000 ng/mL, particularly approximately 100 to 1500 ng/mL. Oral doses to achieve these therapeutic levels are approximately 10 to 2,500 mg of the complex per day, particularly approximately 100 to 750 mg per day. The complex is preferably administered in single dose form, but may be administered in multiple doses per day. The complex also is preferably administered at least one hour before meals and at least two hours after meals, but other schedules are also acceptable.

[0041] Treatment of Mycobacterial Infection

[0042] One embodiment of the invention involves treating a patient infected by a prokaryote of the genus Mycobacterium by administering to the patient a therapeutically effective amount of a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone. The neutral 3:1 (hydroxypyrone:gallium) complex is one in which the 3-hydroxy-4-pyrone is selected from the group of compounds represented by Formula 1, as defined above. The therapeutically effective amount is such that a blood plasma gallium concentration is achieved that is sufficient to enable beneficial treatment of the infection.

[0043] Of particular interest is treatment of those patients that have been infected with Mycobacterium tuberculosis or Mycobacterium leprae.

[0044] In an exemplary dosing regimen, a patient infected by a prokaryote of the genus Mycobacterium preferably will be given about 100 to 750 mg/day of the complex for about 30 to 365 days or longer, the actual duration of therapy being determined by the specific infection to be eradicated. Another exemplary dosing regimen, for example for treatment of M. tuberculosis includes administration of 150 to 750 mg/day for about 30 to 180 days. Yet another exemplary dosing regimen, for example for treatment of M. leprae includes administration of 150-750 mg/day for about 30 to 365 days.

[0045] Optionally, it may be desired to include additional therapeutic agents with the neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone. Such additional agents include, by way of example and not limitation, one or more antimicrobial agents. Exemplary antimicrobial agents are those that have a known efficacy against one or more mycobacteria species. These include amikacin, aminosalicylic acid, azithromycin, capreomycin, ciprofloxacin, clarithromycin, clofazimine, cycloserine, dapsone, erythromycin, ethambutol, ethionamide, isoniazid, kanamycin, minocycline, ofloxacin, protionamide, pyrazinamide, rifabutin, rifampicine, rifampin, sparfloxacin, streptomycin, trimethoprim sulfamethoxazole, tobramycin, and viomycin, and combinations thereof. Particularly preferred are combinations of one or more agents selected from the group consisting of ethambutol, isoniazid, pyrazinamide, rifampin, and streptomycin. The term “antimicrobial agent” is intended to include the compounds identified above, as well as their pharmaceutically acceptable isomers, salts, hydrates, solvates, esters, and prodrug derivatives, e.g., isoniazid hydrazide.

[0046] Treatment of mycobacterial infection in combination with existing therapies

[0047] Another embodiment of the invention involves an improved method of treating a patient infected by a prokaryote of the genus Mycobacterium by administering to the patient a combination of antimicrobial agents selected from the group consisting of amikacin, aminosalicylic acid, azithromycin, capreomycin, ciprofloxacin, clarithromycin, clofazimine, cycloserine, dapsone, erythromycin, ethambutol, ethionamide, isoniazid, kanamycin, minocycline, ofloxacin, protionamide, pyrazinamide, rifabutin, rifampicine, rifampin, sparfloxacin, streptomycin, trimethoprim sulfamethoxazole, tobramycin, and viomycin; the improvement comprising administering a therapeutically effective amount of a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone. The neutral 3:1 (hydroxypyrone:gallium) complex is one in which the hydroxypyrone is selected from the group of compounds represented by Formula 1, as defined above. The therapeutically effective amount is that which achieves a blood plasma gallium concentration that is sufficient to facilitate the antimicrobial combination therapy.

[0048] Of particular interest is treatment of those patients that have been infected with Mycobacterium tuberculosis or Mycobacterium leprae.

[0049] Particularly preferred for co-administration with the gallium hydroxypyrone complex are combinations of one or more agents selected from the group consisting of ethambutol, isoniazid, pyrazinamide, rifampin, and streptomycin.

[0050] Treatment of mycobacterial infection in an immunocompromised patient

[0051] Another embodiment of the invention involves treating an immunocompromised patient infected by a prokaryote of the genus Mycobacterium by administering to the patient a therapeutically effective amount of a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone. The neutral 3:1 (hydroxypyrone:gallium) complex is one in which the hydroxypyrone is selected from the group of compounds represented by Formula 1, as defined above. The therapeutically effective amount is that which provides a blood plasma gallium concentration that is sufficient to facilitate the antimicrobial combination therapy, while not creating any additional complications in the immunocompromised patent.

[0052] Of particular interest is treatment of those patients that have been infected with species such as M. tuberculosis and M. leprae , as well as species such as M. avium, M. aurum, and M. smegmatis , which may pose a health risk to immunocompromised patients.

[0053] In an exemplary dosing regimen, an immunocompromised patient infected by a pathogenic species of Mycobacterium will be given about 100 to 750 mg/day of the complex, for about 30 to 365 days, or longer. In addition, it may be desired to include additional therapeutic agents with the neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone in the treatment of an immunocompromised patient. Such additional agents include, by way of example and not limitation, one or more antimicrobial agents listed previously herein.

[0054] The complex may also be co-administered with other therapeutic agents that the immunocompromised patient may already be taking. These include, by way of illustration and not limitation, antiretroviral agents, particularly those used in AIDS therapy, including without limitation nucleoside analogs such as zidovudine (AZT), ddI and ddC; protease inhibitors such as saquinavir, ritonavir, indinavir, and nelfinavir; and non-nucleoside reverse transcriptase inhibitors such as nevirapine and delavirdine; and so forth. In considering combination therapy, it is important to evaluate how the various therapeutic agents might interact. Many of the aforementioned drugs are nucleoside analogs, which inhibit polymerization of DNA as it is replicated. Gallium is expected to work synergistically with these nucleoside analogs. Gallium inhibits ribonucleotide reductase, and thus inhibits the production of the nucleosides required for DNA synthesis. As a result, the relative proportion of nucleoside analogs to native nucleosides will increase, which will further inhibit bacterial and retroviral DNA synthesis.

[0055] The treatment of an immunocompromised patient with a gallium complex containing a 3-hydroxy-4-pyrone is not limited to those patients whose immunodeficiency is associated with retroviral infection (such as patients with HIV infection). The gallium complexes of the present invention can also be effectively administered to other classes of patients with an immunocompromised status, such as those undergoing organ transplant or those suffering from an immunodeficiency of genetic origin.

[0056] An acknowledged advantage of combination therapy is that it reduces the emergence of resistant strains, due to the low probability of a single organism simultaneously acquiring multiple mutations that would confer resistance to each of the administered agents. The greater the structural and mechanistic differences between the combined agents, the lower the likelihood that simultaneous multiple resistance-conferring mutations will arise. As a primary mechanism of gallium action is novel (the disruption of bacterial iron uptake and metabolism), the addition or substitution of gallium to an existing combination therapy regimen therefore reduces the probability that drug resistance will develop.

[0057] Prevention of Mycobacterial Infection

[0058] Another embodiment of the invention involves the prophylactic treatment of a patient to prevent infection by a prokaryote of the genus Mycobacterium by administering to the patient a prophylactically effective amount of a neutral 3:1 gallium complex of a 3-hydroxy-4pyrone. The neutral 3:1 (hydroxypyrone:gallium) complex is one in which the hydroxypyrone is selected from the group of compounds represented by of Formula 1, as defined above. The therapeutically effective amount is such that a blood plasma gallium concentration is provided that is sufficient to enable prevention of the infection.

[0059] Of particular interest is the prevention of infection with Mycobacterium tuberculosis . The method of the invention can be used to administer a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone to uninfected individuals, including but not restricted to patients that are known to have been exposed to M. tuberculosis or to individuals or patients who may come in contact with infected individuals, such as social workers, health care professionals, and so forth.

[0060] In an exemplary dosing regimen, a prophylactically effective dose will be about 20 to 500 mg/day of the complex, for about 30 to 180 days, which is the time frame needed for effective prophylaxis. In another exemplary dosing regimen, a preventative dosage against a mycobacterial species is about 150 to 750 mg/day of the complex, for about 30 to 180 days.

[0061] It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, the foregoing description, as well as the examples that follow, are intended to illustrate and not limit the scope of the invention. Other aspects, advantages, and modifications will be apparent to those skilled in the art to which the invention pertains.

[0062] All patents, patent documents, and publications cited herein are hereby incorporated by reference in their entirety for their disclosure concerning any pertinent information not explicitly included herein.